This research is concerned with metabolic alterations in the brain resulting from the amino acid imbalances that occur in experimental models of hyperphenylalaninemia and phenylketonuria. These conditions will be produced in young rats by acute or chronic parenteral administration of loading doses of phenylalanine alone, or phenyl-alanine in combination with the metabolic inhibitor of liver phenylalanine hydroxylase, Alpha-methylphenylalanine. Comprehensive studies will be conducted on processes involved in the regulation of protein metabolism and function in regions of the central nervous system exhibiting profound neuropathological defects in hyperphenylalaninemia. Emphasis will be placed on alterations in metabolic processes which may contribute to hypomyelination, delayed or incomplete synaptogenesis and neurotransmission defects in the brain. In view of our earlier observations that certain protein kinase activities are decreased in brains of hyperphenylalaninemic animals, the metabolic processes investigated will include phosphorylation of structural brain proteins that appear to play important roles in neurotransmission; i.e., (a) specific constituents of synaptic membranes, (b) microtubule-associated protein, and (c) myelin basic proteins. Attention will also be given to the basic biochemical processes responsible for the inhibition of protein phosphorylations in the brain in experimental hyperphenylalaninemia, including (a) the nature of the protein kinases responsible, (b) the sensitivity of these protein kinases to inhibition by phenylalanine or its metabolites in vitro and (c) the mechanisms underlying the alterations in protein kinase activities. Since protein phosphorylations play vital roles in many phases of brain metabolism, it is anticipated that these investigations will help to elucidate the mechanisms involved in the production of metabolic abnormalities which contribute to brain dysfunction in human phenylketonuria.